The pathophysiology of diabetes mellitus in all of its forms is ultimately due to a deficiency in insulin signaling. Insulin is responsible for regulating the circulating concentration of energy substrates by stimulating uptake in peripheral tissues and by suppressing gluconeogenesis in the liver. Insulin receptors (Irs) are central to insulin action, and thus, defects in receptor or in post-receptor signaling contribute to the metabolic consequences of insulin resistance. Defects in the IR gene in humans and in transgenic mice leads to severe ketoacidosis. To analyze the contribution of each of the insulin-responsive tissues to whole body metabolism, we have initiated a tissue-specific disruption of the IR gene using the Cre recominase-LoxP system. Adipose is a peripheral organ that is responsible for insulin stimulated glucose uptake and insulin-stimulated fatty acid storage. I propose to use previously generated strains of mice which carry "floxed" IR alleles and an adipose specific Cre-recombinase transgene to explore the role of insulin in adipose tissue is to regulate the metabolism of non carbohydrate energy substrates and that dysregulation of insulin signaling in adipose would result in hyperlipacidemia with subsequent glucose intolerance.